Physiotherapy

doi: 10.2522/ptj.
20080114
Originally published online September 18, 2008
2008; 88:1297-1321. PHYS THER.
Eric Arthur Gulve
Challenges, and Adjustments to Pharmacotherapy
Exercise and Glycemic Control in Diabetes: Benefits,
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Exercise and Glycemic Control in
Diabetes: Benets, Challenges, and
Adjustments to Pharmacotherapy
Eric Arthur Gulve
Exercise, along with dietary intervention, represents rst-line therapy for diabetes
mellitus. Aerobic exercise is recommended for its benecial effects on glucose
control as well as its abilities to retard the progression of other comorbidities
common in patients with diabetes, such as cardiovascular disease. The capability of
aerobic exercise to improve glycemic control in diabetes is well documented, al-
though adherence to exercise regimens is problematic. More recently, the glucose-
lowering effects of resistance training have also been documented; this form of
exercise has additional benets, such as the capability to counteract sarcopenia,
which is common in older people with type 2 diabetes. Exercise in people with
diabetes, however, also can present signicant challenges to glycemic control. Ex-
cessive glucose lowering can occur under certain conditions, enhancing the threat of
hypoglycemia; in other situations, hyperglycemia can be accentuated. An understand-
ing of the interactions between specic antidiabetic medications and various forms
and intensities of exercise is essential to optimizing glycemic control while minimiz-
ing the potential for acute derangements in plasma glucose levels. Exogenous forms
of insulin and agents that stimulate insulin secretion in a glucose-independent manner
(such as sulfonylureas and glinides) increase the propensity for hypoglycemia during
low- to moderate-intensity aerobic exercise. In contrast, exercise protocols charac-
terized by high intensity are more likely to result in episodes of hyperglycemia.
Strategies to minimize inappropriate swings in glycemic control are reviewed.
EA Gulve, PhD, is employed by
BioGenerator, 893 N Warson Rd,
St Louis, MO 63141 (USA). Ad-
dress all correspondence to Dr
Gulve at: gulve@biogenerator.org.
[Gulve EA. Exercise and glycemic
control in diabetes: benets, chal-
lenges, and adjustments to phar-
macotherapy. Phys Ther. 2008;88:
12971321.]
2008 American Physical Therapy
Association
Diabetes
Special Issue
Post a Rapid Response or
nd The Bottom Line:
www.ptjournal.org
November 2008 Volume 88 Number 11 Physical Therapy f 1297
E
xercise and diet are cornerstones
of therapy in diabetes mellitus.
In most patients with diabetes,
the addition of pharmacologic therapy
is required for the management of
plasma glucose levels. In type 1 dia-
betes, the etiology of which involves
the autoimmune destructionof insulin-
producing pancreatic -cells, exoge-
nous insulin (ie, from a source other
than the patients own -cells) is ab-
solutely required. Therapy consists
of the administration of various insu-
lin preparations designed to meet
basal and meal-associated insulin re-
quirements.
1,2
In recent years, sev-
eral new insulin analogs with unique
properties have been developed;
these include short-acting insulin an-
alogs that can be taken just before
meals. These insulin analogs differ in
their pharmacokinetic properties,
such as their rate of appearance in
the bloodstream and how long they
remain in the plasma (Tab. 1).
Type 2 diabetes is characterized by
resistance to the actions of insulin
in the presence of defects in insulin
secretion. Absolute insulin levels vary
with the severity of the disease; early
stages tend to be characterized by a
compensatory hyperinsulinemic state,
but progressive -cell failure eventu-
ally occurs in most patients, leading to
low absolute levels of circulating insu-
lin. Several oral and non-insulin-based
injectable therapies that act on differ-
ent organ systems have been devel-
oped in an effort to modulate glucose
homeostasis (Tab. 2). These therapies
include agents that regulate endoge-
nous insulin secretion (ie, drugs that
stimulate the patients own -cells to
secrete more insulin), dampen he-
patic glucose production, enhance pe-
ripheral glucose metabolism, slow the
gastrointestinal processing of food
and ultimately the absorption of glu-
cose, reduce secretion of the counter-
regulatory hormone glucagon, or com-
binations of these. A review of these
therapies is beyond the scope of this
article, given that the primary con-
cerns during exercise in people with
diabetes are related to the use of ex-
ogenous insulin and insulin secreta-
gogues. Many people with type 2 dia-
betes use insulin secretagogues, and
most eventually progress to a re-
quirement for exogenous insulin ther-
apy.
3
Detailed reviews of available
antidiabetic medicines are available
elsewhere.
4,5
To understand the challenge of blood
glucose regulation in diabetes, one
must consider the various organs that
collaborate in the regulation of blood
glucose levels in health and disease. A
full review is beyond the scope of this
article, but for the purposes of this
review, key organ systems to consider
are skeletal muscle, liver, and the en-
docrine pancreas.
6
Skeletal muscle
represents, quantitatively, the primary
site of insulin-mediated glucose dis-
posal. The liver is the primary organ
that both stores glucose after food in-
gestion and dispenses glucose to the
circulation between meals in order to
maintain appropriate plasma glucose
levels. Fasting plasma glucose levels
(ie, sampled 8 hours or more after the
last meal) are 80 to 100 mg/dL
(4.5mM5.5mM) in young adults
who are healthy. Insulin is released
from pancreatic -cells in response to
the ingestion of food and, in turn, stim-
ulates glucose uptake and storage in
muscle and adipose tissue while simul-
taneously suppressing hepatic glucose
production (Fig. 1). These actions pre-
vent large increases in plasma glucose
levels after a meal in people who are
healthy, because they result in the ef-
cient processing of glucose. In con-
trast, diabetes mellitus is characterized
by exaggerated plasma glucose levels
after a meal and, as the disease pro-
gresses, by increases in plasma glucose
levels in the fasting state. Diabetes mel-
litus is diagnosed in 1 of 3 ways
7
:
Fasting plasma glucose level at or
above 126 mg/dL (7.0mM)
Random plasma glucose level (irre-
spective of time elapsed since the
last meal) at or above 200 mg/dL
(11.1mM) combined with symptoms
of diabetes, such as frequent urina-
tion, excessive thirst, rapidweight loss,
or any combinationof these symptoms
Plasma glucose level at or above
200 mg/dL (11.1mM) when mea-
sured 2 hours after an oral load of
75 g of glucose
Table 1.
Pharmacokinetic Proles of Various Insulin Preparations
Class Insulin Type
a
Onset Peak Duration
Rapidly acting analogs Insulin aspart 520 min 13 h 35 h
Insulin lispro 520 min 12 h 35 h
Insulin glulisine 1020 min 11.5 h 35 h
Short-acting human Regular 3060 min 24 h 48 h
Intermediate-acting human NPH 13 h 410 h 1018 h
Long-acting analogs Insulin detemir 12 h None (at) 24 h
Insulin glargine 24 h None (at) 24 h
a
NPHisophane insulin (neutral protamine Hagedorn).
Exercise and Glycemic Control in Diabetes
1298 f Physical Therapy Volume 88 Number 11 November 2008
The development of multiple thera-
peutic approaches to the treatment
of both type 1 and type 2 diabetes
has enhanced the capacity to main-
tain blood glucose levels closer to
treatment goals. Tight control of
blood glucose levels signicantly re-
duces the incidence of diabetic com-
plications,
810
as reviewed else-
where in this series. However, the
availability of various therapeutic
choices also imposes on the patient
and health care provider the need to
better understand how these thera-
pies act in order to anticipate poten-
tial undesirable consequences of ex-
ercise sessions. Studies of tight
glycemic control in sedentary peo-
ple with diabetes have illustrated the
undesirable effect that occurs as
plasma glucose levels are regulated
closer to goal levelsthat is, an in-
creasing propensity for hypoglyce-
mia.
4,7
Neurons rely on glucose as
their primary energy source. When
plasma glucose levels fall below the
lower limit of fasting values (ie, be-
low70 mg/dL [4mM]), central ner-
vous system function is impaired.
Symptoms, which include irritability,
confusion, dizziness, slurred speech,
lethargy, and blurred vision, become
progressively more severe as blood
glucose levels continue to decrease.
If blood glucose levels become very
low, seizures and coma can occur.
Other symptoms of hypoglycemia
are secondary to defense systems
that attempt to counteract the de-
cline in blood glucose through acti-
vation of the sympathetic nervous sys-
tem. These symptoms include tremor,
sweating, hunger, and increased heart
rate.
Exercise in people with diabetes also
presents challenges to glycemic con-
trol. One of the benecial effects of
exercise on glucose homeostasis is a
marked stimulation of blood glucose
utilization during and after exercise,
as reviewed elsewhere in this series.
However, the net effect of exercise
on blood glucose levels in diabetes
depends on several factors, such as
starting levels of glycemia, type and
duration of exercise, and type and
Table 2.
Classes of NonInsulin-Based Antidiabetic Agents
a
Drug Class Example(s)
Primary Mode of Action
or Type of Drug Advantages Disadvantages
Biguanides Metformin Inhibit hepatic glucose output Weight neutral; TG reduction;
generic
GI side effects (nausea,
diarrhea); lactic acidosis
(rare)
Sulfonylureas Glyburide, glipizide,
glimepiride,
chlorpropamide
Insulin secretagogues
(stimulate insulin secretion
in glucose-independent
manner)
Generally well tolerated;
generic
Weight gain; hypoglycemia
Glinides Repaglinide, nateglinide Short-acting insulin
secretagogues
Generally well tolerated; less
hypoglycemic risk than with
sulfonylureas
TID dosing; some
hypoglycemic risk; not
generic
Thiazolidinediones Pioglitazone, rosiglitazone Reduce insulin resistance,
especially in peripheral
tissues
For pioglitazone: benecial
effects on lipids and
positive CV outcomes
demonstrated
Weight and adiposity gain;
uid retention; risk of
congestive heart failure
For rosiglitazone: increased
risk of MI
-Glucosidase inhibitors Acarbose, miglitol Inhibit intestinal carbohydrate
processing
Weight neutral; slow meal-
associated glucose
appearance
GI side effects (atulence,
cramping, diarrhea); TID
dosing; not generic
Amylin analogs Pramlintide Slow gastric emptying;
enhance satiety
Slow meal-associated glucose
appearance
vomiting); injected; TID
dosing; efcacy lower
than that of other classes
Glucagonlike peptide 1
(GLP-1) analogs
Exenatide, liraglutide Enhance meal-associated
insulin release; reduce
glucagon levels; slow
gastric emptying; enhance
satiety
Glucose-dependent effects on
insulin and glucagon
(decreased hypoglycemic
risk); weight loss
vomiting); injected
Dipeptidyl peptidase IV
inhibitors
Sitagliptin, vildagliptin Inhibit degradation of GLP-1
and GIP, raising
endogenous levels of these
hormones
Weight neutral; oral agents
(compare with GLP-1
analogs)
Little clinical experience to
date
a
TGtriglyceride, GIgastrointestinal, TID3 times daily, CVcardiovascular, MImyocardial infarction, GIPglucose-dependent insulinotropic
polypeptide.
timing of antidiabetic medications.
Insulin plays a critical role in regulat-
ing hepatic glucose output during
many (but not all) forms of exercise
and can also modulate peripheral glu-
cose uptake during exercise and re-
covery. Medications that control plasma
insulin levels present the greatest chal-
lenge to the management of plasma
glucose levels when patients with dia-
betes exercise, as outlined below.
Insulin levels are altered by certain
forms of exercise. In people with
diabetes, a failure to adequately ad-
just medications or carbohydrate
supplementation can result in inap-
propriate swings in blood glucose
levels, either too low or too high,
depending on the factors involved.
Acutely, the most serious danger to
the health of a person with diabetes
is hypoglycemia, for the reasons noted
above. However, circumstances that
result in inappropriate elevations in
blood glucose levels (such as exces-
sive carbohydrate supplementation
or too large a reduction in insulin
dosage) also have adverse implica-
tions. Knowledge of the factors that af-
fect glucose metabolism is critical for
designing strategies to minimize inap-
propriate swings in glycemia. Coupled
with frequent self-monitoring of blood
glucose levels, this knowledge can
lessen the likelihood that exercise will
have deleterious effects on glycemic
control.
Effects of Regular
Aerobic Exercise on
Glycemic Control
A full review of studies demonstrat-
ing the power of aerobic exercise in
the management of diabetes is not
provided here; more information can
be obtained from other reviews.
1113
In brief, resting skeletal muscle pre-
fers free fatty acids as an energy
source, particularly in the postab-
sorptive state (ie, periods between
meals, after the most recent meal has
been processed). Exercise induces a
Figure 1.
Dose-response curves for insulin-mediated inhibition of hepatic glucose production and stimulation of whole-body glucose disposal
in people without diabetes. Two key effects of insulin in lowering blood glucose levels are shown. Increases in insulin concentrations
in the blood inhibit the release of glucose from the liver into the circulation (dashed line) and stimulate the uptake of glucose into
insulin-sensitive tissues, such as skeletal muscle and adipose tissue (solid line). In concert, these actions result in reduced levels of
glucose in the blood. Insulin levels are increased after a meal or after a therapeutic intervention, such as insulin injection or
administration of drugs that stimulate insulin secretion from the pancreas (such as sulfonylureas). Insulin levels are presented as those
in the circulatory compartment most relevant for liver or muscle: for whole-body glucose disposal, insulin concentrations in the
systemic circulation are shown, whereas for hepatic glucose output, the dose-response curve is displayed relative to concentrations
in the hepatic portal circulation. Reprinted with permission from Ferrannini E, DeFronzo RA. Insulin actions in vivo: glucose
metabolism. In: Alberti KGMM, DeFronzo RA, Keen H, et al, eds. International Textbook of Diabetes Mellitus. 2nd ed. Chichester, United
Kingdom: John Wiley & Sons Ltd; 1992. Copyright 2005, Wiley.
shift to a mixture of free fatty acids,
glycogen stores, and circulating glu-
cose; the balance among these 3
sources varies with the duration and
intensity of physical activity.
13,14
Circulating glucose is routed into
working skeletal muscle through sev-
eral complementary mechanisms.
13,15
Contraction of skeletal muscle stimu-
lates glucose transport and metabo-
lism into working muscle through
an insulin-independent pathway. Ex-
ercise has additional effects that en-
hance the ability of insulin to activate
glucose transport into muscles that
have exercised; this effect can persist
for many hours after physical activity
has ceased. The delivery of glucose
to working muscle is facilitated by
increased blood ow to exercising
muscles. When aerobic exercise is re-
peated on a regular basis (ie, training),
muscles recruited by the training stim-
ulus undergo additional adaptations
that involve the synthesis of key com-
ponents needed for glucose uptake
and metabolism (eg, the GLUT4 glu-
cose transporter and enzymes, such as
hexokinase, that control the uptake
and metabolism of glucose in muscle).
These responses to exercise facilitate
the clearance of glucose from the cir-
culation and the metabolism of glu-
cose in exercised skeletal muscle
(oxidation during exercise; resynthe-
sis of glycogen stores after exercise
has been completed). In people with
diabetes, plasma glucose levels de-
crease during and shortly after a bout
of exercise. Indexes of long-term gly-
cemic control, such as glycosylated he-
moglobin (HbA1c, the level of which
is elevated in diabetes), are improved
(ie, lowered) when exercise is per-
formed regularly.
1113
Continuous Low- to
Moderate-Intensity Exercise
Glucoregulation During Exercise
in People Without Diabetes
When people who do not have dia-
betes exercise at low to moderate
workloads, plasma glucose levels are
maintained at or near preexercise
levels.
14
Euglycemia (ie, a normal
glucose level) is maintained by close
correlation of peripheral glucose up-
take and hepatic glucose output
across a range of exercise intensities
up to approximately 80% of maximal
oxygen uptake (V
O
2
max). As work-
loads are increased over this range,
muscle glucose uptake increases and
the production of glucose by the
liver is enhanced to a similar extent
16
(Fig. 2). Moderate workloads increase
glucose utilization by about 3 mg/kg of
body weight per minute; if this pro-
cess were not counterbalanced by an
increased hepatic supply of glucose,
then overt hypoglycemia would occur
within about 30 minutes
11
(a theoret-
ical illustration is shown in Fig. 3). Glu-
cose is generated by the liver through
2 processes: (1) mobilization from he-
patic glycogen stores as a result of
glycogenolysis (which predominates
earlier during exercise) and (2) syn-
thesis of new glucose from smaller
precursor molecules through gluco-
neogenesis (which assumes greater
importance as exercise duration in-
creases). Hypoglycemia rarely occurs
in people who do not have diabetes
unless exercise is quite prolonged
that is, when liver glycogen stores
become depleted and the exercise
workload exceeds the ability of glu-
Figure 2.
During exercise at lowto moderate intensity, increases in glucose production are closely
matched by increases in peripheral glucose uptake. Splanchnic glucose production
(representative of liver glucose output) and leg glucose uptake (representative of
peripheral glucose disposal) are shown at rest and at different levels of low- to
moderate-intensity exercise. With each increase in exercise workload, the rate of glu-
cose disappearance (attributable to uptake into the working muscles) was very similar
to the rate of glucose release from the liver (into the blood). As a result, blood glucose
levels remained approximately constant during low- to moderate-intensity exercise. Leg
glucose uptake and splanchnic glucose production are shown for people without
diabetes at rest and after performing cycle ergometer exercise for 40 minutes at
different workloads. Data are expressed as mean SE. Reprinted with permission of the
American Society for Clinical Investigation from Wahren J, Felig P, Ahlborg G, et al.
Glucose metabolism during leg exercise in man. J Clin Invest. 1971;50:27152725.
Copyright 1971.
coneogenesis to meet peripheral
demands.
Figures 4 and 5 illustrate changes in
key hormones and indexes of glu-
cose metabolism during low- to
moderate-intensity exercise (50% of
V
O
2
max, performed for 40 minutes;
open symbols) and during high-
intensity exercise (87% of V
O
2
max,
sustained for 15 minutes; closed
symbols) (the response to high-
intensity exercise is discussed be-
low). The increase in hepatic glu-
cose output observed during low- to
moderate-intensity exercise is con-
trolled primarily by changes in insu-
lin and glucagon secretion. This is a
key point in understanding the chal-
lenges of exercise in diabetes, as dis-
cussed below. Exercise at these in-
tensity levels results in decreased
insulin secretion (likely mediated
mostly by the increase in adrenergic
tone to the pancreas) and increased
glucagon secretion.
17
The decrease
in insulin secretion is thought to be
important for the activation of he-
patic glycogenolysis, and the increase
in glucagon secretion enhances both
glycogenolysis and gluconeogenesis.
In addition, exercise increases the
generation and delivery to the liver of
gluconeogenic precursors. The inter-
action between these 2 pancreatic
hormones is responsible for (nearly)
the entire increase in the liver glucose
supply. For example, the ability of
glucagon to enhance glucose output is
signicantly magnied when insulin
levels are allowed to decline in their
usual fashion during exercise, com-
pared with experimental circum-
stances in which insulin is maintained
at baseline (preexercise) levels.
17
In exercise of relatively short du-
ration, increases in arterial plasma
glucagon levels are quantitatively
modest. It is not the arterial concen-
trations of insulin and glucagon that
control liver glucose output, but
rather the concentrations of these
pancreatic hormones in the hepatic
portal vein, into which they are
secreted.
17
The concentrations of
these 2 hormones are higher in the
portal vein than in the overall sys-
temic circulation. Animal studies (in
which portal vein blood can be
much more readily sampled) have
revealed that alterations in the por-
tal concentrations of these 2 hor-
monesin the range occurring
physiologicallyare the critical de-
terminants controlling hepatic glu-
cose supply during low- to moderate-
intensity exercise.
18,19
If the portal
vein levels of insulin and glucagon
are deliberately xed at preexercise
levels, then moderate-intensity exer-
cise can lead to signicant decreases
in plasma glucose levels.
20
Mechanis-
tically, this result derives, in large
measure, from direct effects of portal
vein insulin and glucagon concen-
trations on the liver. If the usual
exercise-triggered decrease in portal
vein insulin concentrations is ar-
ticially overridden and portal vein
insulin concentrations are instead
increased within the physiological
range (Fig. 6), then the exercise-
induced stimulation of liver glucose
production is instead rapidly and
substantially suppressed.
21
In con-
trast, hyperinsulinemia in the arterial
circulation without a corresponding
increase in the portal vein causes
only a modest and delayed reduction
in hepatic glucose output (most
likely the result of a secondary effect
of insulin [lowering free fatty acid
levels]).
Figure 3.
Theoretical impact on plasma glucose levels of a failure to increase hepatic glucose
production during exercise. Solid lines represent changes in glucose uptake and en-
dogenous (ie, hepatic) glucose production and their impact on plasma glucose levels in
people who were healthy and were performing moderate-intensity exercise. Dashed
lines represent what would ensue if the liver did not increase the rate of glucose
production during the exercise bout. If glucose uptake into the working muscles were
not counterbalanced by a corresponding increase in liver glucose output, then blood
glucose concentrations would decline from baseline levels and could reach hypogly-
cemic levels. Reprinted with permission of the American Diabetes Association from Sigal
RJ, Kenny GP, Wasserman DH, et al. Physical activity/exercise and type 2 diabetes.
Diabetes Care. 2004;27:25182539. Copyright 2004, American Diabetes Association.
Effects of Low- to Moderate-
Intensity Exercise on
Glucoregulation in
People With Diabetes
In patients who have type 2 diabetes
and are taking medications that do
not act by elevating (endogenous or
exogenous) insulin levels, the effect
of low- to moderate-intensity exer-
cise varies with the starting levels of
glycemia. During exercise, patients
with slightly or moderately elevated
glucose levels generally experience a
decline in plasma glucose levels that
does not result in hypoglycemia.
13
The decline in blood glucose levels
under these conditions occurs be-
cause peripheral glucose uptake in-
creases more than hepatic glucose
output.
22
If exercise is superimposed
shortly after a meal has been in-
gested, then the usual meal-induced
increase in glycemia is blunted.
23
For
patients still possessing reasonable
pancreatic function, exercise results
in a decline in blood glucose levels
concomitantly with a decline in
plasma insulin levels.
23
Because muscle contractile activity
stimulates glucose transport activity
partly through an insulin-independent
mechanism,
2427
exercise is useful in
lowering plasma glucose levels in pa-
tients lacking insulin secretary ca-
pacity, displaying insulin resistance,
Figure 4.
Plasma glucose, insulin, and adrenergic hormone levels during and after either moderate- or high-intensity exercise in people without
diabetes. Measurements were obtained in young male subjects at rest, during exercise, and for an additional 2 hours after the
cessation of exercise. A rest period (baseline) was followed by exercise at the 2 durations, as shown between the vertical broken lines.
Subjects exercised for 40 minutes at moderate intensity (50% of maximal oxygen uptake [V
O
2
max]) () or performed 15 minutes
of high-intensity exercise (87% of V
O
2
max) () on a cycle ergometer. A break in the line representing high-intensity exercise was
inserted to allow matching of the postexercise recovery (R) periods (R0R120 minutes) for the 2 exercise protocols. Data are
expressed as mean SE. (A) Plasma glucose. The levels changed very little with moderate-intensity exercise. In contrast, glucose
levels increased sharply with high-intensity exercise, especially during the recovery period. (B) Plasma insulin. A gradual decline in
levels with moderate-intensity exercise and a return to baseline levels during early recovery were observed. With high-intensity
exercise, an initial downward trend was followed by a marked rise during the recovery period. (C and D) Plasma norepinephrine (C)
and plasma epinephrine (D). The levels of both catecholamines increased about 3-fold during moderate-intensity exercise and to a
much greater extent during high-intensity exercise, with a rapid return to baseline levels once exercise was over. The substantial
increases in catecholamine levels that occurred with high-intensity exercise are believed to be critical drivers of hepatic glucose output
(see the text for details). Reprinted with permission of the American Diabetes Association from Marliss EB, Vranic M. Intense exercise
has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes. 2002;51(suppl
1):S271S283. Copyright 2002, American Diabetes Association.
or both, if conditions are appropri-
ately controlled. If people with dia-
betes are ketotic and severely hyper-
glycemic as a result of signicant
insulin underdosing, then exercise
aggravates the existing hyperglyce-
mia. In contrast, if people with ei-
ther type 1
14
or type 2
28,29
diabetes
are adequately treated with insulin
and display mild to moderate hyper-
glycemia, then a session of vigorous
exercise can lower blood glucose
levels.
The potential benecial effects of ex-
ercise on glucose levels are counter-
balanced by potential risks to people
with insulin-dependent diabetes. In
the early 20th century, it was recog-
nized that exercise performed by
people with insulin-decient diabe-
tes under certain conditions could
result in signicant hypoglycemia.
30
Patients with type 1 and type 2 dia-
betes requiring exogenous insulin
therapy, insulin secretagogue ther-
apy, or both face unique challenges
during exercise. Insulin levels in
these patients are derived exclu-
sively or predominantly from their
medications; as a result, they do not
decrease in response to exercise. Pa-
tients whose insulin levels signi-
cantly exceed the fasting baseline
level at the time of exercise tend to
be overtreated with insulin relative
to this physiological challenge (ie,
they operate at inappropriately high
points on their hepatic and muscle
insulin dose-response curves). With-
Figure 5.
Plasma glucagon levels, glucagon-to-insulin molar ratio, hepatic glucose production (GP), and peripheral glucose utilization (GU)
during and after either moderate- or high-intensity exercise in people without diabetes. Measurements were obtained in young male
subjects at rest, during exercise, and for an additional 2 hours after the cessation of exercise. A rest period (baseline) was followed
by exercise at the 2 durations, as shown between the vertical broken lines. Subjects exercised for 40 minutes at moderate intensity
(50% of maximal oxygen uptake [V
O
2
max]) () or performed 15 minutes of high-intensity exercise (87% of V
O
2
max) () on a cycle
ergometer. As in Figure 4, a break in the line representing high-intensity exercise was inserted to permit plotting of the recovery (R)
period (R0R120 minutes) starting from the cessation of exercise. Data are expressed as mean SE. (A) Plasma glucagon. Changes
were minimal at either exercise intensity. (B) Glucagon-to-insulin molar ratio. This ratio increased slightly during exercise (primarily
because of the decrease in insulin levels [Fig. 4B]). This ratio returned to baseline during the recovery period after moderate-intensity
exercise and declined markedly after high-intensity exercise. The latter nding was entirely attributable to postexercise hyperinsu-
linemia (Fig. 4B). (C and D) Rates of GP (C) and GU (D). GP and GU each doubled during moderate-intensity exercise. In contrast,
GP increased 7-fold and GU increased 4-fold during high-intensity exercise (note the different y-axis scales); the greater magnitude
of the increase in GP than of the increase in GU accounted for the hyperglycemia seen with high-intensity exercise. Reprinted with
permission of the American Diabetes Association from Marliss EB, Vranic M. Intense exercise has unique effects on both insulin release
and its roles in glucoregulation: implications for diabetes. Diabetes. 2002;51(suppl 1):S271S283. Copyright 2002, American
Diabetes Association.
out the normal exercise-induced de-
cline in portal vein insulin levels, he-
patic glucose production remains
suppressed and cannot increase suf-
ciently to match the increase in pe-
ripheral glucose utilization. As a result,
blood glucose levels decline, poten-
tially to hypoglycemic levels. Under
these conditions, hypoglycemia can
develop despite adequate hepatic gly-
cogen reservoirs. The situation can be
further exacerbated if peripheral insu-
lin levels are inappropriately elevated;
higher systemic levels of insulin also
stimulate greater glucose uptake into
peripheral tissues, including muscle
beds not activated by exercise.
The importance of prevailing insulin
levels at the time of exercise in peo-
ple who have diabetes and are taking
insulin or insulin secretagogues is
now well recognized. A few selected
examples of data underlying the cur-
rent understanding are discussed.
In a study of adults with diabetes, an
articial endocrine pancreas (AEP) ca-
pable of adjusting the insulin infu-
sion in relation to blood glucose levels
after a meal was used.
31
Subjects
without and subjects with diabetes
were given breakfast; 45 minutes later,
they performed a 45-minute session of
moderate-intensity exercise. Circulat-
ing glucose and insulin levels in sub-
jects with diabetes and using the AEP
mirrored those in subjects without di-
abetes, increasing in response to the
meal and returning to the baseline
(premeal) levels during exercise. In an-
other group of subjects, the AEP was
instead programmed to deliver suf-
cient insulin to respond to the meal
challenge but at a constant rate
throughout the study; that is, the insu-
lin levels were not allowed to decline
during the exercise challenge. In the
latter subjects, the exercise bout re-
sulted in a steady decline in glucose
levels to belowthe premeal level, such
that the subjects experienced symp-
tomatic hypoglycemia.
Studies in children with type 1 dia-
betes conrmed the risk of exercise
under conditions in which exogenous
insulin levels are not adjusted. For ex-
ample, in subjects treated with a sub-
cutaneous insulin infusion designed
to bring preexercise glucose levels
into the normal range, a 45-minute
moderate-intensity exercise session
during which the insulin infusion rate
was kept constant resulted in a sub-
stantial further decrease in blood glu-
cose levels, leading to hypoglycemia,
in a signicant proportion of subjects.
32
In another study, the effect of
moderate-intensity aerobic exercise
(treadmill walking in 15-minute seg-
ments totaling 60 minutes of activ-
ity) designed to mimic after-school
activity, performed in the afternoon 4
hours after a lunch meal, was eval-
uated.
33
Children and adolescents
treated with either an insulin pump or
a combination of basal and short-
acting insulin analogs were studied on
both a rest day and an exercise day.
Insulin regimens were deliberately
kept the same on the 2 study days.
On the exercise day, 83% of the sub-
jects experienced a decline in plasma
glucose levels of at least 25% from
the baseline (average drop of 40%
across all subjects). Hypoglycemia
Figure 6.
Insulin excess in the hepatic portal circulation suppresses hepatic glucose production during
exercise more rapidly and to a much greater extent than elevated insulin levels in the
systemic circulation. Insulin levels in dogs were manipulated through pharmacological
suppression of endogenous production followed by replacement in either the hepatic
portal or the peripheral circulation. Dogs were studied at rest (30 to 0 minutes) and
during moderate-intensity treadmill exercise. During the rest period, insulin was replaced at
basal levels (ie, those seen in the fasting, sedentary state). During the rst 60 minutes of
exercise, insulin was replaced to levels normally seen during exercise (ie, insulin levels were
gradually reduced, as during moderate-intensity exercise). During the nal 90 minutes of
exercise, this simulation was continued () or increased to create mild hyperinsulinemia in
the peripheral circulation alone () or mild hyperinsulinemia in the artery and portal vein
({). Insulin levels higher than those normally present during exercise resulted in reduced
endogenous glucose production ( and {). However, the suppression of liver glucose
output was greatest when insulin levels were increased in the hepatic portal circulation ({),
the blood compartment that receives insulin released from the pancreas and that, in turn,
perfuses the liver. Data are expressed as mean SE. *Signicantly different from corre-
sponding time points in other groups (P.05).
#
Signicantly different from corresponding
time points in dogs with simulated arterial and portal vein insulin replacement (P.05).
Reprinted with permission of Lippincott Williams & Wilkins (http://lww.com) from Cama-
cho RC, Galassetti P, Davis SN, et al. Glucoregulation during and after exercise in health and
insulin-dependent diabetes. Exerc Sport Sci Rev. 2005;33:1723. Copyright 2005, American
College of Sports Medicine.
was common (30% of the subjects
had plasma glucose levels of 60
mg/dL or required glucose adminis-
tration during or after exercise) and
relatively rapid in onset (33% of ep-
isodes occurred within 30 minutes
on the exercise day). The lower the
baseline glucose levels were, the
greater the proportion of children
who experienced hypoglycemia.
In contrast to the critical role of por-
tal vein hormones in controlling liver
glucose output, it is the peripheral
concentration of insulin that stimu-
lates glucose uptake into muscle
and adipose tissue after meals and
into previously activated muscle -
bers when insulin sensitivity has
been enhanced by exercise. Thus,
the type of insulin replacement and
its relative effect on portal versus sys-
temic insulin levels affect glycemic
control after exercise.
Several factors can contribute to dys-
regulated glucose control during and
for several hours after exercise in
insulin-treated patients, as outlined
by Camacho et al
17
:
The lack of a decline in insulin se-
cretion during exercise inappropri-
ately accentuates the effects of in-
sulin on the liver and peripheral
tissues
Exercise can accelerate the absorp-
tion of insulin injected at a subcu-
taneous site located near the mus-
cles used during exercise
The exercise-mediated enhance-
ment of the action of insulin mag-
nies the consequences of inappro-
priately elevated insulin levels
during exercise as well as in the
postexercise period, when insulin
sensitivity can remain enhanced for
many hours; the net effect depends
partly on the pharmacokinetics of
the particular insulin preparation
or insulin secretagogue used
In addition to the threat posed by
excessively high insulin levels during
exercise, it is now recognized that
when people experience episodes of
hypoglycemia before a bout of exer-
cise, their ability to subsequently
mount counterregulatory responses
to impending hypoglycemia during
exercise is blunted, rendering them
more susceptible to exercise-induced
hypoglycemia.
34,35
Conversely, pro-
longed endurance exercise sessions
can impair the counterregulatory re-
sponses to subsequent hypoglycemic
challenges.
34,35
The latter phenome-
non, combined with the induction by
exercise of a prolonged enhancement
in insulin sensitivity, may be an impor-
tant contributor to the hypoglycemia
seen during the evening after an after-
noon exercise session in people with
insulin-dependent diabetes.
36
Minimizing Hypoglycemic
Events During Low- to
Moderate-Intensity Exercise in
Patients Taking Insulin
For patients who have type 1 diabe-
tes as well as those who have type 2
diabetes and require exogenous in-
sulin, there is no single recommen-
dation specifying adjustments for ex-
ercise. The glycemic response to
physical activity and the propensity
for hypoglycemia during or after an
exercise session are inuenced by
several factors
3740
:
Type of insulin (or insulin combi-
nations) and corresponding phar-
macokinetic and pharmacodynamic
properties
Time elapsed since last insulin dose
Form of administration (injection,
inhalation, or insulin pump)
Injection site and proximity to ex-
ercising limbs
Type, duration, and intensity of
exercise
Amount of muscle mass involved in
the activity
Level of physical tness
Preexercise glucose levels
Patency of counterregulatory re-
sponses
With carbohydrate supplementation:
type of carbohydrate (simple or com-
plex), rate of absorption, and timing
of administration
Because of the complexity of factors
that can inuence glucose utiliza-
tion, guidelines must be relatively
general in nature. Appendix 1 lists
factors to consider in initiating an
exercise program. Discussed below
are some key points.
As a rst step in the initiation of an
exercise regimen or sporting activ-
ity, patients should be assessed for
conditions that might contraindicate
certain types of exercise or that
could increase the risk of specic
types of injury.
7,13,37
These condi-
tions include cardiovascular risk fac-
tors (because diabetes can enhance
the propensity for cardiovascular
disease in the presence of known
risk factors), autonomic and periph-
eral neuropathies, and retinopathy.
The presence of risk factors or dia-
betic complications should not pre-
clude the use of an exercise pro-
gram. When such conditions are
present, exercise plans can still be
prescribed but should be tailored to
lessen the specic risks involved.
For example, people at high risk of
cardiovascular disease should be en-
couraged to begin with short pe-
riods of low-intensity exercise and
then gradually increase the duration
and intensity of their exercise ses-
sions. Patients with autonomic neu-
ropathy should perform only light
exercise until a more thorough car-
diac evaluation has been performed.
For additional information on exer-
cise in these pathologies, see the ar-
ticle by Cade
41
in this issue. Patients
with peripheral neuropathy are at
higher risk of problems when per-
forming weight-bearing activities,
but nonweight-bearing activities,
such as cycling, swimming, or upper-
body exercise, can be prescribed.
For additional information on exer-
cise for people with diabetes and
peripheral neuropathy, see the arti-
cle by LeMaster et al
42
in this issue.
Even patients with signicant renal
impairment requiring dialysis can be
encouraged to use modalities appro-
priate for specic aspects of their
disease.
37
Once an exercise program has been
chosen, patients can prepare for
their exercise sessions. Glucose lev-
els should be checked shortly before
patients begin exercise sessions. To
minimize the risk of uncontrolled hy-
perglycemia, if blood glucose levels
are greater than 250 mg/dL and uri-
nary ketone body levels are moder-
ate or high (indicating that insulin
levels are very low), then the exer-
cise session should be postponed un-
til appropriate therapeutic measures
have minimized ketone production
and reduced glucose levels.
7,39
Even
if ketone levels are not high, when
blood glucose levels exceed 300 mg/
dL, patients should consider post-
poning exercise until blood sugar
levels are brought under better con-
trol. Likewise, patients should not
exercise when blood glucose levels
are too low. Supplemental carbohy-
drates should be administered if pre-
exercise glucose concentrations are
less than 100 mg/dL.
7
When patients are adjusting to a new
exercise program, blood glucose lev-
els should be checked shortly be-
fore, during (if practical), and imme-
diately after the exercise session.
Because exercise can result in a long-
lasting enhancement of insulin ac-
tion, additional checks should be
made several hours after the exercise
has been completed. Measurements
should be repeated with each exer-
cise session until the typical glyce-
mic response to a given activity is
understood. Even after a regular rou-
tine has been established, periodic
checks should be performed be-
cause changes in factors such as diet,
medication, and body weight can in-
uence blood glucose levels. Signi-
cant alterations to the usual exercise
pattern (such as type of sport, dura-
tion, and intensity) also necessitate
additional checks of the blood glu-
cose prole.
If the exercise results in overt hypo-
glycemia or a tendency for hypogly-
cemia, then the insulin dose should
be adjusted, carbohydrate supple-
mentation should be given, or both.
For exercise planned in advance,
several options are available:
The dose of insulin can be reduced
beforehand
Injections can be made distant from
the exercising limbs
Carbohydrates can be ingested be-
fore exercise, during exercise, or
both
All of these strategies can be com-
bined; it should be recognized that
these strategies are dependent on
each other; for example, insulin dose
reductions should be smaller if un-
dertaken concomitantly with carbo-
hydrate supplementation. For exer-
cise not planned in advance (which
is particularly common in children),
carbohydrate supplementation is the
only practical option unless patients
use an insulin pump; in the latter
situation, the rate of insulin infusion
can be decreased or the pump can
be turned off entirely.
43
It is beyond the scope of this discus-
sion to review all of the studies that
have evaluated issues such as various
exercise protocols, insulin regimens,
timing of exercise onset relative to
medications, and carbohydrate sup-
plementation. A few examples are
presented to help readers under-
stand the issues.
In a common diabetes treatment reg-
imen, a long-acting insulin is admin-
istered to meet basal insulin require-
ments over a prolonged time period,
accompanied by meal-associated ad-
ministration of a short-acting insulin.
If the patient has already adminis-
tered a normal dose of a fast-acting
insulin analog, then it is preferable to
avoid exercise for several hours. In
one study, the effects of regular in-
sulin and the short-acting analog in-
sulin lispro, taken at their standard
premeal intervals in adults with type
1 diabetes, were compared.
44
When
exercise was initiated 40 minutes af-
ter breakfast, insulin lispro lowered
glucose levels 2.2-fold more than reg-
ular insulin; that is, the fast-acting
analog showed more-pronounced
glucose lowering at a time associated
with its peak levels in plasma. In con-
trast, when exercise was performed
3 hours after breakfast (a time at
which the levels of the analog in
plasma are known to be substantially
lower than peak levels), insulin lis-
pro lowered glucose levels only half
as much as regular insulin.
An alternative approach is to reduce
the dose of short-acting insulin if ex-
ercise is to be performed during a
time period when levels of the ana-
log in plasma will be elevated.
Rabasa-Lhoret et al
45
evaluated the
effects of different reductions in in-
sulin lispro doses and different exer-
cise intensities in a small number of
adults who had well-controlled type
1 diabetes and who began exercising
90 minutes after a breakfast meal.
Because the patients already had
achieved good control (mean HbA1c
of 6.1%), the investigators targeted a
postexercise plasma glucose level
that was similar to the premeal level.
Exercise intensity was varied from
25% to 75% of V
O
2
max. Even at the
lowest exercise workload (25% of
V
O
2
max for 60 minutes), hypogly-
cemia ensued when the normal dose
of lispro was not adjusted, and a 50%
dose reduction provided optimal
postexercise glycemia (Fig. 7). The
magnitude of the dose reduction
needed for optimal glucose control
increased with both the intensity
and the duration of exercise. When
exercise at an intensity of 50% of
V
O
2
max was performed for 30 min-
utes, a 50% dose reduction was op-
timal; when exercise was sustained
for 60 minutes, however, a 75% de-
crease in the dose resulted in opti-
mal glycemia immediately after exer-
cise. Under these conditions, the
optimal dose reduction for a given
intensity or duration of exercise was
associated with a 75% reduction in
hypoglycemic episodes, compared
with the results obtained for exer-
cise without a change in the dose.
That study
45
also highlighted one of
the challenges of insulin dose reduc-
tion strategies: The reduction in the
dose needed to avoid excessive hy-
poglycemia during exercise may not
be optimal once exercise is com-
plete. Decreases in the lispro dose
resulted in rebound increases in gly-
cemia during the recovery period
after exercise (Fig. 7); the greater the
magnitude of the dose reduction, the
greater the elevation in glucose lev-
els during recovery. This complica-
tion is difcult to avoid in people
Figure 7.
Changes in plasma glucose levels in subjects with type 1 diabetes before, during, and after exercise at different intensities and
durations and with various levels of reductions in the dose of insulin lispro (LP). Young males with type 1 diabetes on a basal-bolus
insulin regimen were treated just before the ingestion of a standardized breakfast meal with their usual full dose of LP (LP 100%) or
xed percentages of this dose on different occasions. At 90 minutes after the meal, they performed cycle ergometer exercise (o) for
30 or 60 minutes at different intensities. (Left) Subjects exercised at 25% (A) and at 50% (B) of maximal oxygen uptake (V
O
2
max)
for 60 minutes after premeal LP 100% (E), LP 50% () (ie, a 50% reduction in insulin dose), and LP 25% () (ie, a 75% reduction
in insulin dose). (Right) Subjects exercised at 50% (C) and at 75% (D) of V
O
2
max for 30 minutes after premeal LP 100% (E), LP 50%
(), and LP 25% (). The shaded area represents mean SEM postprandial plasma glucose levels at rest. Reductions in the LP dose
resulted in higher meal-associated increases in plasma glucose levels (increases seen before the onset of exercise) but lessened the
tendency for exercise to result in decreases in blood glucose levels to belowthe premeal (time 0) level. Generally speaking, the greater
the increase in exercise duration, intensity, or both, the greater the exercise-induced decrease in plasma glucose levels and, therefore,
the more the insulin dose should be reduced to avoid decreases in plasma glucose levels from the premeal level. Data are expressed
as mean SEM. *P.05, as determined by repeated-measures analysis of variance. Reprinted with permission of the American
Diabetes Association from Rabasa-Lhoret R, Bourque J, Ducros F, et al. Guidelines for premeal insulin dose reduction for postprandial
exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen
(Ultralente-Lispro). Diabetes Care. 2001;24:625630. Copyright 2004, American Diabetes Association.
with insulin-dependent diabetes, who
lack the normal minute-to-minute
control of endogenous insulin secre-
tion that is present in people who do
not have diabetes. Modest postexer-
cise increases in glucose levels, how-
ever, are far less dangerous than
serious hypoglycemic episodes.
For patients using traditional mix-
tures of isophane insulin (neutral
protamine Hagedorn) and regular in-
sulin, the morning insulin dose can
be reduced for planned exercise ses-
sions. Exercise sessions in the higher
range of moderate intensity require
correspondingly larger dose reduc-
tions. For example, in one study,
when adults with type 1 diabetes be-
gan exercising for 1 hour at 70% of
V
O
2
max 90 minutes after breakfast,
50% to 90% reductions in the morn-
ing insulin dose were needed to
avoid exercise-related hypoglycemia.
46
For patients using insulin pumps, an
additional option is to reduce the
rate of insulin infusion during exer-
cise. This option can be particularly
helpful when basal insulin is the pri-
mary regulator of glycemia (eg, when
it has been many hours since the last
administration of a meal-associated
insulin bolus, such as exercise in
the late afternoon). In one study,
the effect of variations in pump rate
was examined in children perform-
ing moderate-intensity afternoon ex-
ercise for 1 hour.
47
Treadmill walking
was undertaken on 2 different days
to compare the effect of maintaining
the basal pump rate with that of turn-
ing off the insulin pump completely.
Hypoglycemia was common when
the pump was used at normal rates;
in contrast, exercise-related hypogly-
cemia was signicantly reduced on
days when subjects turned off the
pump. In that scenario, the pump
was not turned back on until 45 min-
utes after the cessation of exercise.
On both days, glucose levels gradu-
ally rebounded after exercise was
stopped, but on the day when the
pump was turned off, there was a
greater propensity for glycemia to ex-
ceed the preexercise baseline. This
situation is analogous to that dis-
cussed above with lispro dose re-
ductions; however, with a pump, an
insulin infusion can be resumed
shortly after exercise has ended.
The use of carbohydrate supplemen-
tation to minimize the occurrence of
hypoglycemia during and after exer-
cise has been examined in several
studies. As discussed for other inter-
ventions, such as alterations in insu-
lin doses, an understanding of the
conditions under which the studies
were performed is needed to extrap-
olate ndings to specic exercise
bouts; these conditions can include
insulin dose reductions, intensity
and duration of exercise, and timing
of exercise relative to the last medi-
cation. For example, in one study,
subjects with type 1 diabetes were
given breakfast 30 minutes after a
normal morning injection of regular
insulin; at time intervals ranging
from 1 to 5.5 hours later, they began
a 60-minute moderate-intensity (50%
of V
O
2
max) exercise session.
48
The
amount of carbohydrate supplemen-
tation required to prevent the devel-
opment of hypoglycemia decreased
as the time interval before the com-
mencement of exercise increased;
the reduction in the need for carbo-
hydrate supplementation paralleled
the gradual reduction in plasma insu-
lin levels.
When a similar exercise protocol
was initiated 3 hours after breakfast
in subjects continuing their standard
basal-bolus regimen (NPH and insu-
lin lispro), it was concluded that car-
bohydrate supplementation of 40 g
was needed to maintain the desired
glucose levels during exercise and
the rst hour of recovery.
49
Like-
wise, a study of exercise in children
indicated that an older recommenda-
tion for 15 g of carbohydrate can be
inadequate in preventing hypoglyce-
mia when the insulin dose has not
been adjusted.
33
In the aforementioned studies, car-
bohydrate requirements in patients
who ate breakfast and did not alter
their usual insulin dose were exam-
ined. In contrast, if patients with type
1 diabetes exercise in the morning
after skipping their normal morning
insulin dose (resulting in low plas-
ma insulin levels), moderate-intensity
exercise for 45 minutes may result
in only a small reduction in plasma
glucose levels. Under these condi-
tions, carbohydrate supplementation
can actually result in signicant in-
creases in plasma glucose levels dur-
ing exercise.
50
For patients who do
not skip but instead reduce their in-
sulin dose, an intermediate level of
carbohydrate supplementation is ap-
propriate. Suggestions for carbohy-
drate requirements and insulin dose
reductions based on exercise inten-
sity and duration have been pro-
posed (eg, by Grimm et al
51
), but
these should be considered merely
potential starting points, to be mod-
ied on the basis of specic exercise
conditions and on empirical mea-
surements of glycemia. In addition,
recommendations that minimize the
practice of insulin dose reduction
and rely primarily on the use of car-
bohydrate supplementation will lead
to higher overall caloric intake; if
common, this practice will negate
the benets of exercise to increase
energy expenditure and stimulate
weight loss.
Children can undergo large varia-
tions in physical activity levels that
are sustained for many days or weeks,
such as during school holiday periods.
For those with insulin-dependent dia-
betes, sudden and sustained increases
in energy expenditure can impose sig-
nicant challenges to glycemic con-
trol. Strategies for optimizing glycemic
control in settings such as summer di-
abetes camps have been examined in
several studies. For example, in one
camp at which participants engaged in
signicant levels of physical activity,
frequent episodes of hypoglycemia
occurred despite signicant (30%)
reductions in daily insulin doses.
52
Re-
peated monitoring of blood glucose
levels, increases in meal portions, and
carbohydrate supplementation were
all recommended.
In summary, real-world adjustments
must be made on an empirical basis
for each patient and pattern of phys-
ical activity. When possible, it is im-
portant to either delay exercise dur-
ing anticipated times of peak insulin
levels or make appropriate adjust-
ments. Supplemental carbohydrate in
a form that is rapidly absorbed should
be kept on hand in the event of a hy-
poglycemic episode. More details,
3739
including a checklist of issues to con-
sider,
40
are outlined elsewhere.
Minimizing Hypoglycemic
Events During Low- to Moderate-
Intensity Exercise in People
Who Have Type 2 Diabetes and
Are Taking Medications
Other Than Insulin
Insulin secretagogues. Various in-
sulin secretagogues and related prep-
arations (eg, extended-release formu-
lations) have been developed for use
in type 2 diabetes. They differ in their
pharmacokinetics and pharmacody-
namics, that is, the timing of insulin
appearance in and disappearance
from the circulation as well as the
duration of their effects. Thus, guide-
lines for their use with exercise can-
not be generalized. Published data
on the tendency of exercise to re-
sult in hypoglycemia have sometimes
yielded apparently conicting results.
Critical to the interpretation of re-
sults are the specic conditions under
which studies were conducted, such
as the starting levels of glycemia; the
duration, mode, and intensity of exer-
cise; the pharmacokinetic and phar-
macodynamic properties of the secre-
tagogue; and the timing of exercise
onset after the dose of medicine. For
example, in a study of an extended-
release form of glipizide, the effects
of exercise in subjects who had dia-
betes and exercised at a very light
workload for 90 minutes were eval-
uated.
28
Under these conditions and
with relatively high starting levels
of glucose, this form of glipizide did
not induce hypoglycemia. The glucose-
lowering effect of this exercise proto-
col was modest, however, as shown
for a control group of subjects who
had diabetes but were not treated with
glipizide; that is, the exercise chal-
lenge was slight, with a buffer of
relatively high initial glucose levels.
In another study, the effects of the
sulfonylurea glibenclamide were eval-
uated in patients exercising for 60
minutes at moderate intensity.
29
The
same group of patients was studied
after drug treatment alone, exercise
alone, or a combination. The combi-
nation of glibenclamide and exercise
lowered blood glucose levels more
than either intervention alone. Circu-
lating insulin levels were higher and
the exercise-induced increase in he-
patic glucose output was smaller
with the combination protocol than
with exercise alone. Preexercise glu-
cose levels were high (180 mg/dL);
the patients did not experience hy-
poglycemia, but the authors appro-
priately noted that had exercise con-
tinued, the patients would have had
a greater likelihood of reaching hypo-
glycemia in the combination trial.
29
These data are entirely consistent
with the view that relative hyperin-
sulinemia during exercise acceler-
ates the decrease in plasma glucose
levels.
Ultimately, a critical factor for pa-
tients taking insulin secretagogues is
the level of insulin in the blood at
the time of exercise, just as it is in
patients taking exogenous insulin.
An empirical determination of the
dosage adjustment for a given exer-
cise regimen should be undertaken
initially. Additional monitoring of
blood glucose levels before, during,
and after exercise is recommended
whenever an exercise regimen is sig-
nicantly modied. Patients who are
achieving tight control of blood glu-
cose levels are, in turn, at greater
hypoglycemic risk and should con-
sider a reduction in medication dos-
age under conditions in which insu-
lin levels would be relatively high
during the exercise period. For un-
planned exercise after medication
has already been ingested, carbohy-
drate supplementation during exer-
cise, after exercise, or both is recom-
mended, particularly for patients in
whom preexercise glucose levels are
already relatively low (100 mg/dL).
In addition, there are less-common
genetically inherited forms of diabe-
tes in which the response to secre-
tagogues and hence exercise can dif-
fer from that of most people with
type 2 diabetes.
53
Other medications. For patients
who have type 2 diabetes and who
have achieved reasonably good gly-
cemic control, guidelines indicate
that medications other than insulin
and insulin secretagogues do not re-
quire special adjustments for exer-
cise.
7
Drugs that act primarily by
enhancing peripheral insulin action
do not display a signicant tendency
for hypoglycemia because they do not
act at steps that would interfere with
the counterregulatory responses to
impending hypoglycemia.
54
One ex-
ception may be for patients who re-
ceive metformin therapy and who
have severe hepatic insufciency or
after excessive intake of alcohol.
54
The
reason is that hepatic dysfunction un-
der these conditions compromises the
ability of the liver to generate glucose;
because metformin acts primarily
through the suppression of hepatic
glucose production, patients in this
category have a substantially reduced
ability to prevent an onset of impend-
ing hypoglycemia.
Published data on the interactions of
exercise and several other glucose-
lowering medications are lacking,
particularly for newer classes of ther-
apy, such as glucagonlike peptide 1
analogs and dipeptidyl peptidase IV
inhibitors. These agents have multi-
ple effects (Tab. 2), but their efcacy
is driven mostly by the potentiation
of meal-induced insulin secretion
and the suppression of glucagon re-
lease.
55
Both of these effects are glu-
cose dependent; that is, the effects
of glucagonlike peptide 1 diminish
with decreasing plasma glucose levels
(unlike the ability of sulfonylureas
and glinides to stimulate insulin se-
cretion). Therefore, in the sedentary
state, they have been shown to re-
duce the propensity for hypoglyce-
mic episodes. The current assump-
tions are that they also lessen the
tendency for exercise-induced hypo-
glycemia and that adjustments for
exercise are not needed.
54
Continuous High-
Intensity Exercise
Glucoregulation During
High-Intensity Exercise in
People Without Diabetes
In people who do not have diabe-
tes, euglycemia is not maintained as
exercise intensity increases. High-
intensity exercise, generally dened
as a workload requiring greater than
80% of V
O
2
max, is characterized by
increases in plasma glucose levels
(Fig. 4, closed symbols). After the
cessation of exercise, glucose levels
generally continue to increase and
reach a peak during the immediate
postexercise period. During recov-
ery from such strenuous exercise,
the restoration of glucose to preex-
ercise levels can take up to 1 hour.
56
High-intensity exercise increases the
rates of hepatic glucose output and
peripheral glucose uptake to greater
extents than low-intensity exercise.
Elevations in plasma glucose levels
result from the fact that, unlike the
situation with lighter workloads,
with high-intensity exercise the in-
crease in hepatic glucose production
exceeds that of peripheral glucose
disposal.
56
Glucose production can
increase by as much as 8-fold from
resting rates, an increase that is as
large as that seen in any physiologi-
cal condition or pathological state.
The primary mechanism controlling
hepatic glucose production shifts as
exercise reaches more-strenuous lev-
els (Figs. 4 and 5). Insulin secretion
decreases to a lesser extent with high-
intensity exercise than with moderate-
intensity exercise or is maintained at
basal levels. The absence of a marked
reduction in insulin levels may be sec-
ondary to the prevailing hypergly-
cemia (a prime stimulus for insulin
secretion), to a reduction in insulin
degradation, or both.
56
The increase in
glucagon secretion during strenuous
exercise remains modest (or, more
precisely, the increase in the hepatic
portal glucagon-to-insulin ratio is mod-
est) and is insufcient to account for
the massive stimulation of hepatic glu-
cose output (although it likely con-
tributes to some hepatic production).
The change in growth hormone is not
essential, and the modest increase in
glucocorticoid levels (a steroid whose
actions are exerted only after a time
lag) is inconsistent with the kinetic
aspects of the response, that is, the
rapidity of the increase in hepatic glu-
cose output.
Data fromseveral different experimen-
tal approaches have suggested that
catecholamines are the primary driv-
ers of the enhanced hepatic glucose
production observed during high-
intensity exercise.
56
During moderate-
intensity exercise, catecholamine con-
centrations increase 2- to 4-fold above
resting values; in contrast, circulating
epinephrine and norepinephrine con-
centrations are elevated 10- to 20-fold
during high-intensity exercise (Fig. 4).
Increases in the circulating levels of
both epinephrine and norepinephrine
are probably required for the full stim-
ulation of glucose production. The ad-
ministration of either catecholamine
by itself (to levels commensurate with
those seen during high-intensity exer-
cise) stimulates hepatic glucose out-
put partially,
5760
but only a combi-
nation of the 2 catecholamines can
augment this process to levels ap-
proaching those observed with stren-
uous exercise.
61
The role of hepatic
sympathetic neural stimulation is
equivocal; some authors
59,62
have sug-
gested that it is not essential, whereas
other authors
61
have suggested that
the interpretation of those particular
studies is complicated.
Substantial elevations in plasma cate-
cholamine levels also may explain the
observation that the hepatic produc-
tion of glucose exceeds the peripheral
utilization during high-intensity exer-
cise, as others previously showed that
catecholamines can partially inhibit
the uptake of glucose into muscle and
adipose tissue.
57,58,63,64
In both people
without and people with diabetes, a
good correlation was demonstrated
between circulating catecholamine
levels and the net differential between
hepatic glucose production and pe-
ripheral glucose uptake.
65
In a series of
studies of people who were healthy,
glucose uptake across the leg was eval-
uated in the presence or absence of
added arm exercise.
66,67
The addition
of arm exercise (which increased total
workload and resulted in substantial
elevations in plasma catecholamine
levels) reduced glucose uptake across
the working leg in comparison with
uptake in the absence of added arm
exercise. Combined arm work and leg
work increased liver glucose output
more than peripheral glucose disposal
and increased plasma glucose levels.
However, the importance of overall
adrenergic control of hepatic function
during strenuous exercise is not fully
understood. The inability of an adren-
ergic blockade to fully block glucose
production during exercise at high
workloads has led some researchers to
postulate that additional control mech-
anisms may be important.
17
Thus, high-intensity exercise presents
an exception with regard to the con-
trol of hepatic glucose production,
which is regulated under many cir-
cumstances primarily by insulin and
the glucagon-to-insulin ratio. High-
intensity exercise can stimulate sharp
increases in hepatic glucose output
even under circumstances normally as-
sociated with the suppression of glu-
cose production. For example, when
glucose production is attenuated at
rest by interventions such as glucose
infusion
68
or carbohydrate-containing
meals
69
(which both result in eleva-
tions in endogenous insulin levels in
people without diabetes), the subse-
quent imposition of high-intensity ex-
ercise still results in a substantial in-
crease in liver glucose production (as
well as the increase in circulating cat-
echolamine levels). This hierarchy of
control is important: Although most
experimental investigations of glucose
metabolism have been performed in
the overnight fasting state, in practice
people exercise much of the time in
some phase of the absorptive state,
that is, when endogenous glucose pro-
duction is still at least partially sup-
pressed as a result of a recent meal. A
common example is the participation
of children in after-school sports pro-
grams. These control mechanisms
make it possible for the insulin-
dependent suppression of liver glu-
cose output to be overridden during
high-intensity exercise, protecting
people with diabetes from develop-
ing severe hypoglycemia.
Glucoregulation During Recovery
from High-Intensity Exercise in
People Without Diabetes
Plasma glucose levels peak shortly af-
ter the conclusion of a high-intensity
exercise bout and then begin to return
to baseline levels (Fig. 4A). Hepatic
glucose output and peripheral glucose
disposal decline fairly rapidly (Fig. 5).
Glucose uptake initially reverses more
quickly than hepatic output, result-
ing in further hyperglycemia, which
is gradually reversed over a 1- to
2-hour period.
56
Signicant increases
in insulin levels occur shortly after
the cessation of high-intensity exer-
cise (Fig. 4B), likely reecting a re-
sponse to the prevailing hypergly-
cemia in combination with a rapid
withdrawal of -adrenergic suppres-
sion of insulin secretion.
High-intensity exercise leads to rapid
depletion of glycogen stores in con-
tracting muscle bers. It has been
suggested that the hyperglycemic-
hyperinsulinemic setting that occurs
immediately after high-intensity ex-
ercise may be important in promot-
ing rapid initial rates of glycogen
replenishment in depleted bers.
56
This feature would be particularly
important in activities characterized
by multiple bouts of repeated high-
intensity exercise, such as soccer or
ice hockey. The more persistent en-
hancement of insulin action induced
by muscle contraction likely contrib-
utes to further relling of glycogen
stores after plasma glucose and insu-
lin have returned to baseline levels.
15
What factors govern the rate of de-
cline in glucose production and up-
take during the initial recovery pe-
riod after high-intensity exercise? A
study in which insulin levels were
manipulated during the recovery pe-
riod indicated that insulin is not the
primary factor controlling the rapid
reversal of hepatic glucose produc-
tion.
65
More likely, the rapid shutoff
of hepatic glucose output (Fig. 5C,
closed symbols) is controlled by the
rapid decline in circulating cate-
cholamines, which precedes the re-
versal of hepatic output (possibly
with an additional contribution from
the shutoff of hepatic sympathetic
neural stimulation). With regard to
peripheral glucose metabolism, rates
of glucose utilization decline when
exercise ends. Although the decline
in plasma glucose levels is not abso-
lutely dependent on the hyperinsu-
linemic environment, variations in
plasma insulin levels modulate the
rate of return of glucose uptake.
Studies in which insulin levels were
manipulated during the recovery pe-
riod indicated that elevations in
plasma insulin levels are associated
with higher rates of decline in blood
glucose levels because of a pro-
longed period of enhanced periph-
eral glucose uptake,
65,68,69
as would
be expected on the basis of knowl-
edge of the interactions between insu-
lin and contractile activity.
Effects of High-Intensity
Exercise on Glucoregulation
in People With Diabetes
Although there is an abundance of
published literature describing the
effects of low- to moderate-intensity
exercise on glucose regulation in
people with type 2 diabetes, there
have been surprisingly few studies of
high-intensity exercise in this popu-
lation. This fact is unfortunate, given
the high prevalence of type 2 diabe-
tes. The scarcity of published studies
partly reects the demographic char-
acteristics of the type 2 population,
which make high-intensity exercise
much more challenging to perform
(people in this population are older,
obese, more sedentary, and have low
physical tness, often coupled with
contraindications such as cardio-
vascular risk factors). Thus, most of
the data on high-intensity exercise in
diabetes derives from studies of
younger and more physically t peo-
ple with type 1 diabetes. It is not
clear whether all of the observations
derived from studies of young peo-
ple with type 1 diabetes can be ex-
trapolated to other populations of
people with diabetes.
The shift in the control of glucoregu-
lation with high-intensity exercise
(compared with exercise at lower in-
tensities) presents both comforting
and complicating aspects for people
with diabetes. Processes regulated
by insulin-independent mechanisms
are generally preserved when people
with diabetes engage in high-intensity
work; these processes include nor-
mal increases in glucose production
and disposal during and immediately
after exercise as well as a normal rate
of decline in glucose production af-
ter exercise. Because glucose pro-
duction is controlled primarily by
catecholamines, current data suggest
that physically t patients with insulin-
dependent diabetes can exercise vig-
orously and engage in competitive
sports requiring high-intensity work-
loads; they are less likely to develop
hypoglycemia under these condi-
tions than when they engage in low-
intensity exercise. More data on re-
sponses to high-intensity exercise
are needed for older, less-t people
with type 1 diabetes and for people
with type 2 diabetes. One study of
people with type 2 diabetes sug-
gested that they develop hypergly-
cemia during extremely vigorous
exercise.
70
In fact, they may have a
propensity for more rapid and larger
increases in plasma glucose levels
than people without diabetes, driven
by exaggerated catecholamine re-
sponses and more rapid increases in
hepatic glucose production.
70
Fac-
tors controlling plasma glucose lev-
els during high-intensity exercise are
summarized in Appendix 2.
Appropriate control of glycemia dur-
ing the postexercise recovery pe-
riod is more challenging because of
the role of insulin in modulating the
postexercise decline in glucose dis-
posal. In the recovery period after
a high-intensity exercise bout, the
strategies for avoiding inappropriate
glucoregulation are distinctly differ-
ent from those used after exercise at
lower intensities. At lower intensi-
ties, a prime concern is to avoid hy-
poglycemia, whereas after strenuous
exercise, the prevailing milieu is one
of hyperglycemia. Strategies designed
to mitigate the development of hypo-
glycemia (such as enhanced carbohy-
drate consumption or reduced insulin
dose), important for low-intensity ex-
ercise, can exacerbate hyperglycemia
after high-intensity exercise. Patients
with insulin-dependent diabetes can-
not generate hyperinsulinemia of en-
dogenous origin, normally important
for enhancingtherateof returnof post-
exercise hyperglycemia to the base-
line. Thus, low circulating levels of in-
sulin (or carbohydrate supplementation
or both) can prolong hyperglycemia
during the recovery period, partially
counteracting the benecial effects
of exercise on glucose control. If
people nd that their activity pat-
terns lead to prolonged postexercise
hyperglycemia, consideration should
be given to the administration of in-
sulin shortly after the completion of
a high-intensity exercise session.
56
Appendix 3 summarizes key factors
that control the recovery from hy-
perglycemia after the cessation of
high-intensity exercise.
Given a choice, it is much more pru-
dent to err on the side of elevated
glucose levels than hypoglycemia,
but optimal glycemic management
over the long term in patients who
have diabetes and who exercise reg-
ularly requires an appreciation of the
different effects of low-intensity ex-
ercise and high-intensity exercise on
glycemic control. This knowledge, in
turn, leads to different strategies
for appropriately managing glucose
levels with exercise. As noted above,
the absolute level of glycemia de-
pends on several factors, such as pre-
exercise glucose and insulin levels,
type of insulin used, timing of insulin
administration relative to pharmaco-
kinetic properties, and site of insulin
injection. If people perform high-
intensity exercise on a regular basis,
then slightly smaller increases in blood
glucose
71
and catecholamine
72,73
lev-
els will be observed (in comparisons
of bouts of the same absolute work-
load) as a result of adaptations to
training.
Intermittent High-
Intensity Exercise
In most studies investigating glucoreg-
ulation during exercise in people with
diabetes, exercise protocols character-
ized by a constant intensity level have
been used.
22,23,28,29,31,32,4346,4850,53
Although certain sports, such as en-
durance running, often involve exer-
cise at a sustained intensity level, this
is not always the case (eg, interval
training workouts). Other sports, inpar-
ticular, many team sports, such as soc-
cer, football, or baseball, are character-
ized by intermittent levels of exertion:
periods of low- to moderate-intensity
exercise punctuated by brief outputs
of high-intensity effort. This type of
activity also is more characteristic of
spontaneous play in children.
Given that continuous high-intensity
exercise in people with diabetes has
effects quite different from those
of low-intensity activity, several re-
cent studies have evaluated the ef-
fects of exercise protocols involving
intermittent bursts of high-intensity
work. In a series of studies of young
adults with type 1 diabetes, Guel and
colleagues
74,75
used exercise proto-
cols designed to approximate the
ratio of high-intensity effort to low-
intensity effort (or recovery) char-
acteristic of many team sports. The
experiments were designed to re-
ect conditions that would lead to
large reductions in glycemia if low-
intensity exercise had been per-
formed; that is, subjects were asked
to administer their usual morning
dose of insulin (no adjustment for
exercise), and activity was initiated
during a period when plasma insulin
levels were high. In control experi-
ments, continuous exercise at 40%
of peak oxygen uptake (V
O
2
peak)
resulted in signicant decreases in
plasma glucose levels (Fig. 8). The
imposition of 4-second maximal
sprints repeated every 2 minutes
lessened the decline in plasma glu-
cose levels and maintained glucose
at signicantly higher levels during
recovery (Fig. 8).
74
Similar protective
effects were seen when subjects per-
formed intermittent maximal sprints
with complete rest in between.
75
Despite the fact that the intermit-
tent protocol was characterized by a
greater amount of total work and
higher oxygen uptake, the periodic
sprint bouts did not lead to more-
pronounced hypoglycemia. The
mechanism for the protective effect
of the intermittent high-intensity
protocol was then examined.
76
Com-
pared with the protocol involving
continuous exercise at 40% of V
O
2
peak, the intermittent sprint pro-
tocol stimulated a more rapid in-
crease in hepatic glucose produc-
tion, which was maintained at higher
levels during exercise. This was
more than enough to offset a modest
increase in peripheral glucose dis-
posal. The greater stimulation of liver
glucose output, in turn, was associ-
ated with higher catecholamine lev-
els, but not with any differences in
insulin or glucagon levels.
7476
These
ndings are consistent with cate-
cholamines driving the higher he-
patic glucose output and perhaps
limiting the increase in muscle glu-
cose uptake, but that hypothesis has
not been directly evaluated for this
intermittent exercise paradigm.
These ndings suggest that activities
characterized by intermittent high-
intensity exercise may have less of a
tendency for hypoglycemia than ac-
tivities characterized by only contin-
uous low-intensity exercise. These
principles could be deliberately used
as a strategy to avoid hypoglycemia
when people are performing contin-
uous low- to moderate-intensity ex-
ercise, that is, with the periodic in-
sertion of brief high-intensity efforts.
In a follow-up study, the effects of a
single maximal sprint performed at
the end of a session of exercise at
40% of V
O
2
peak in subjects with type
1 diabetes were evaluated.
77
On one
day, the subjects rested at the end of
the exercise session; on that occa-
sion, glucose levels continued to de-
crease during the 2-hour recovery
period. On an alternative day, the sub-
jects performed a 10-second maximal
sprint at the end of the exercise ses-
sion (which caused catecholamine
and lactate levels to rise sharply); glu-
cose levels quickly stabilized and were
signicantly higher during the recov-
ery period than when the sprint was
not performed (Fig. 9).
The deliberate use of intermittent high-
intensity sprint bouts is best suited for
children and relatively young adults;
it would be more impractical for
older, less-t people (and more likely
to be contraindicated). Nevertheless,
it represents an additional strategy for
mitigating the likelihood of hypogly-
cemia in some people. In practice, the
effects of superimposing brief high-
intensity efforts should be determined
empirically with frequent glucose mon-
itoring. Further experimental studies
of intermittent exercise regimens are
warranted.
Figure 8.
Effects of intermittent high-intensity exercise (IHE) and moderate-intensity exercise
(MOD) on glycemic control in subjects with type 1 diabetes. Young males and females
with type 1 diabetes were treated with their usual morning dose of insulin just before
the ingestion of a standardized breakfast meal. At 3.5 hours after insulin injection,
subjects participated in 1 of 2 different cycle ergometer exercise protocols (shaded
box). The MOD protocol (E) consisted of 30 minutes of continuous cycling at 40% of
maximal oxygen uptake. The IHE protocol (F) consisted of continuous cycling inter-
spersed every 2 minutes with 4-second maximal sprint efforts designed to simulate the
activity patterns of common team sports (16 sprints in total). Plasma glucose (A) and
insulin (B) levels were monitored before, during, and for 90 minutes after exercise. The
substantial decrease in plasma glucose levels that occurred during continuous
moderate-intensity exercise could be attenuated by interjecting occasional brief sprint
bouts. Results are expressed as mean SE.
a
Statistically signicant difference (P.05)
from resting value.
b
Statistically signicant difference (P.05) between IHE and MOD
values. BGLblood glucose level. Reprinted with permission of the American Diabetes
Association from Guel KJ, Jones TW, Fournier PA. The decline in blood glucose levels
is less with intermittent high-intensity compared with moderate exercise in individuals
with type 1 diabetes. Diabetes Care. 2005;28:12891294. Copyright 2005, American
Diabetes Association.
Resistance Exercise
As noted above, aerobic exercise
programs can be challenging for
many people with diabetes, such as
people with signicant obesity, peo-
ple with very low levels of aerobic
tness, or elderly patients with sar-
copenia, severe arthritis, or both. For
others, aerobic exercise may be con-
traindicated because of the presence
of diabetic complications, such as
cardiovascular disease or advanced
peripheral neuropathy. Exercise pro-
grams based on progressive resis-
tance training represent an alterna-
tive mode of exercise for these
patients as well as a supplementary
form of exercise for patients with
diabetes in general.
Progressive resistance training offers
multiple benets to patients, such as
increasing muscle mass and strength
(force-generating capacity), increas-
ing energy expenditure, reducing vis-
ceral adipose tissue, improving lipid
proles, increasing bone density, and
counteracting the age-related tendency
for sarcopenia.
78,79
Resistance train-
ing, particularly programs that empha-
size high-intensity sessions with corre-
spondingly lower aerobic aspects, can
be used for patients who have dif-
culty performing aerobic exercise or
who have specic contraindications.
78
Few published longitudinal studies of
the benets of resistance exercise for
glycemic control in diabetes had ap-
peared a decade ago. After that time,
several small studies, performed mostly
with subjects who had type 2 diabetes
and, in many cases, lacking randomiza-
tion of subjects, had suggested that
resistance training improved various
indexes of glycemic control (for de-
tails, see discussions elsewhere
13,7880
).
These studies were followed by sev-
eral randomized controlled trials with
subjects who had type 2 diabetes, in
which resistance training programs
lasting 4 to 6 months resulted in im-
provements in glycemic control in the
same range as that shown for aerobic
exercise programs.
81,82
Several factors may contribute to the
improvement in glycemic control
seen with resistance exercise train-
ing programs: (1) increases in mus-
cle mass, which provide a larger res-
ervoir for glucose disposal; (2) direct
effects on skeletal muscle that in-
crease glucose transport activity; and
(3) improvements secondary to a
loss of adipose tissue (in particular,
visceral adipose tissue, which is
known to be a contributor to insulin
resistance). Determining the relative
contributions of each of these fac-
tors is challenging. The direct effects
of resistance exercise on muscle glu-
cose uptake were evaluated in a
study in which people who were
healthy and patients with type 2 di-
abetes trained only one leg.
83
Mea-
surements of glucose uptake and glu-
cose transporter content in each leg
demonstrated increased GLUT4 glu-
cose transporter density per unit of
muscle in the strength-trained leg.
Glucose clearance in the trained leg
was also increasedand to a greater
extent than could be explained by
the increased muscle mass of the
Figure 9.
Effects on glycemic control of a 10-second maximal sprint after moderate-intensity
exercise in subjects with type 1 diabetes. Young male subjects with type 1 diabetes were
treated with their usual morning dose of insulin just before the ingestion of a standard-
ized breakfast meal. At 2 h after insulin injection (20 minutes), subjects initiated 20
minutes of continuous cycle ergometer exercise at 40% of maximal oxygen uptake (o).
On one occasion (control trial), they rested at the end of the moderate-intensity exercise
period (E). On the other occasion (sprint trial), they performed a 10-second all-out
sprint () at the end of the continuous exercise period (F). Blood glucose levels were
measured before, during, and for 120 minutes after completion of the exercise trials,
and data are expressed relative to those obtained immediately after the moderate-
intensity exercise (time 0). A single short sprint of supramaximal intensity may be
sufcient to interrupt the decline in blood glucose levels that occurs with continuous
moderate-intensity exercise. All data are expressed as mean SE.
b
P.05 versus
0-minute time point (after moderate-intensity exercise) in control trial.
c
P.05 versus
0-minute time point (after moderate-intensity exercise) in sprint trial. Reprinted with
permission of the American Diabetes Association from Bussau VA, Ferreira LD, Jones TW,
et al. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in
glycemia in individuals with type 1 diabetes. Diabetes Care. 2006;29:601606. Copy-
right 2006, American Diabetes Association.
trained leg. Thus, the results of that
study
83
demonstrated that local ad-
aptations in skeletal muscle, similar
to the well-known effects of endur-
ance exercise protocols, is an impor-
tant contributor to improvements in
glucose homeostasis in people who
have diabetes and undergo resis-
tance exercise training. These effects
should add to the benets associated
with increases in total muscle mass.
Other studies have demonstrated
that exercise programs combining
aspects of both endurance training
and resistance training can lead to
signicant improvements in indexes
of glycemic control,
84,85
including at
least one small study of adolescents
with type 1 diabetes.
86
In one re-
cently published study, the effects of
aerobic training and resistance train-
ing singly and in combination were
evaluated.
87
The authors reported
that although each program inde-
pendently lowered HbA1c levels in
patients with type 2 diabetes, the
combination training regimen was
signicantly more effective than ei-
ther exercise mode alone. Interpre-
tation of the results is complicated
by the fact that the combination
training regimen was characterized
by a much greater total duration of
exercise; thus, it cannot be deduced
whether the greater benet resulted
from the increased exercise duration
or the combination of the 2 different
types of exercise. Nevertheless, that
study
87
afrmed that these 2 types of
exercise can be combined in an ef-
fort to add variety to workouts and
attain benets, such as increased
muscle strength, that are comple-
mentary to those provided by aero-
bic exercise alone. (See the article by
Marcus et al
88
in this issue for a study
of combined aerobic and resistance
exercise intervention in people with
diabetes.)
Professional organizations, such as
the American College of Sports Med-
icine and the American Diabetes As-
sociation, now recommend that re-
sistance training be included in the
treatment of diabetes.
7,89
The litera-
ture on resistance exercise training,
however, provides very little discus-
sion of the frequency of hypoglyce-
mia associated with weight training,
nor are there specic recommenda-
tions regarding changes in diabetes
medications.
Conclusion
Both aerobic and resistance exercise
programs have the potential to im-
prove glycemic control in diabetes.
Aerobic exercise confers additional
benets to the heart and vasculature;
resistance exercise counters age-
related sarcopenia and provides other
benets. Aerobic exercise sessions must
be carefully managed in patients with
diabetes treated with exogenous insu-
lin or insulin secretagogues because of
the importance of insulin concentra-
tions in regulating glucose metabolism
during low- to moderate-intensity ex-
ercise and during recovery from exer-
cise. An understanding of the factors
that contribute to hypoglycemia or hy-
perglycemia is essential to the proper
use of exercise programs.
Several important areas will benet
from additional research. The dearth
of published data addressing poten-
tial interactions between antidiabetic
medications and exercise in type 2
diabetes is surprising, given the fact
that exercise and dietary modica-
tion are the rst-line therapeutic in-
terventions. More studies are needed
to characterize the effects of differ-
ent exercise intensities on glycemic
control in type 2 diabetes (eg, exer-
cise programs used by specic pop-
ulations, such as elderly people). Data
are needed to strengthen the under-
lying assumption that special precau-
tions are not needed for exercise in
patients who have type 2 diabetes
and are taking medications other than
insulin or insulin secretagogues. For
type 1 diabetes, more data on the hy-
poglycemic and hyperglycemic poten-
tials of exercise are needed for older
people, who are much less t than the
younger people who are usually the
subjects of studies of type 1 diabetes.
Studies of potential sex differences re-
lated to exercise in diabetes are gener-
ally lacking as well.
Additional studies of exercise proto-
cols that more closely approximate
the activity patterns of common sports
are needed (eg, intermittent exertion
with various intensity levels and rest
periods). What combinations of inten-
sity levels and rest intervals trigger a
switch from glucose-lowering effects,
with a concomitant threat of hypo-
glycemia, to a setting characterized
by hyperglycemia? Is the propensity
of high-intensity exercise to generate
hyperglycemia reduced with repeated
exercise sessions, given that catechol-
amine levels tend to be lowered by
training? Is the potential for prolonged
exercise to impair counterregulatory
responses to a subsequent hypoglyce-
mic challenge reduced when exercise
is performed on a regular basis?
Regarding resistance training, there is
a need for a more detailed evaluation
of the frequency of either hypogly-
cemia or hyperglycemia. What are the
relative benets of various forms of
resistance training (eg, powerlifting,
bodybuilding, and circuit training)?
What levels of training frequency and
intensity are needed to derive minimal
as well as maximal benets? Of par-
ticular interest to physical therapists,
who often prescribe resistance exer-
cises for specic muscle groups, is
how much muscle mass must be en-
gaged to derive training-induced gly-
cemic benets or, alternatively, pose
a threat of hypoglycemia? Answers to
questions such as these will provide
more-specic guidelines for exercise
prescriptions and will enable people
with diabetes to derive more of the
potential glycemic benets of
exercise.
This article was submitted April 16, 2008, and
was accepted July 7, 2008.
DOI: 10.2522/ptj.20080114
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Appendix 1.
Initiating an Exercise Program for People With Diabetes
a
Assess underlying conditions that might contraindicate specic exercise protocols
Assess severity of conditions and tailor specic exercise prescriptions that minimize specic risks
For example, presence of cardiovascular risk factors, neuropathies, retinopathy, nephropathy, vascular disease,
or ulcers in the lower extremities
Check blood glucose levels regularly
If 250 mg/dL shortly before exercise, check urinary ketones
If ketones are moderate to high, administer insulin and postpone exercise bout until ketones return to low levels
and glucose levels are 250 mg/dL
If ketones are low but glucose is 300 mg/dL, consider treating with appropriate antidiabetic medication and
postponing exercise until glucose is 250 mg/dL
If glucose is 100 mg/dL shortly before exercise, consider carbohydrate supplementation
Check glucose before, during, and after exercise as often as practical until the patients glycemic response to a given
mode of exercise is understood
Adjust premeal insulin and carbohydrate intake as needed
Reinitiate regular checks of blood glucose whenever signicant changes are made to antidiabetic medicines or
to the exercise program (such as type of exercise, intensity, duration, timing relative to meals, or medicine)
Emphasize the importance of regular exercise
Organizations such as the American Diabetes Association and the American College of Sports Medicine recommend
at least 150 minutes of aerobic exercise per week, performed on at least 3 nonconsecutive days
Two additional sessions of resistance training should be encouraged
The specic exercise programs should be tailored to adjust for risk factors
These recommendations represent long-term goals; identify exercise modalities that the patient will enjoy and
gradually build toward long-term goals
When initiating a program in patients with a history of highly sedentary behavior, divide exercise into 2 or 3
daily 10- to 15-minute sessions
a
For additional details and guidelines, see the text and references therein.
Appendix 2.
Control of Blood Glucose During High-Intensity Exercise
During high-intensity exercise in people without diabetes
Plasma glucose increases
Peripheral glucose uptake increases in working muscles (more so than during low- to moderate-intensity
exercise)
Hepatic glucose production increases (more so than during low- to moderate-intensity exercise)
Increase in hepatic glucose production exceeds increase in peripheral glucose uptake
Shift in control of hepatic glucose production
Changes in insulin and glucagon are no longer dominant
Catecholamines increase to a much greater extent than at lower intensities of exercise and act as primary
regulators of liver glucose output
During high-intensity exercise in people with diabetes
Patients with type 1 diabetes and likely those with type 2 diabetes develop hyperglycemia during high-intensity
exercise
Responses are generally similar to those in people without diabetes
Exercise-induced increases in catecholamines and hepatic glucose output are preserved
Exercise-induced hypoglycemia is not a major concern in people with insulin-dependent diabetes
High catecholamine levels can override the effects of inappropriately high levels of insulin
Appendix 3.
Control of Blood Glucose During Recovery From High-Intensity Exercise
After high-intensity exercise in people without diabetes
Plasma glucose decreases
Generally returns to baseline within 12 h
Hepatic glucose production declines more rapidly than peripheral glucose uptake
The decline in hepatic glucose production is driven primarily by a rapid decline in circulating catecholamines
The decline in peripheral glucose uptake is driven primarily by factors intrinsic to the working muscles
Insulin levels rise soon after the cessation of exercise
Insulin modulates the rate of decline in muscle glucose uptake
Higher levels of insulin during recovery accelerate the decline in blood glucose (ie, prolong the period of
enhanced glucose uptake)
After high-intensity exercise in people with diabetes
Declines in circulating catecholamines and hepatic glucose output are generally similar to those in people without
diabetes
The intrinsic rate of decline in peripheral glucose uptake (ie, that driven by factors in the working muscles) is
generally similar to that in people without diabetes
The rate at which plasma glucose levels return to baseline in patients not requiring exogenous insulin or insulin
secretagogues is generally similar to that in people without diabetes
Factors extrinsic to the working muscles can present challenges in patients requiring exogenous insulin or insulin
secretagogues
Lower levels of insulin during recovery (attributable to a reduction in insulin or insulin secretagogue dosing)
slow the decline in glucose levels and can exacerbate postexercise hyperglycemia
Excessive carbohydrate supplementation accentuates postexercise hyperglycemia
doi: 10.2522/ptj.20080114
Originally published online September 18, 2008
2008; 88:1297-1321. PHYS THER.
Eric Arthur Gulve
Challenges, and Adjustments to Pharmacotherapy
Exercise and Glycemic Control in Diabetes: Benefits,
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